Search

Background: Type 2 diabetes mellitus (T2DM) has been shown to increase the risks of cognitive decline and dementia. Paired box gene 4 (PAX4), a transcription factor for beta cell development and function, has recently been implicated in pathways intersecting Alzheimer's disease and T2DM., Objective: In this report, we evaluated the association of the ethnic-specific PAX4 R192H variant, a T2DM risk factor for East Asians which contributes to earlier diabetes onset, and cognitive function of Chinese T2DM patients., Methods: 590 Chinese patients aged 45-86 from the SMART2D study were genotyped for PAX4 R192H variation using Illumina OmniExpress-24 Array. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) which had been validated in the Singapore population was administered to assess five cognitive domains: immediate memory, visuospatial/constructional, language, attention, and delayed memory. Multiple linear regression was used to assess the association of the R192H risk allele and cognitive domains., Results: Patients with two PAX4 R192H risk alleles showed significantly lower attention index score (β= -8.46, 95% CI [-13.71, -3.21], p = 0.002) than patients with wild-type alleles after adjusting for age, gender, diabetes onset age, HbA1c, body-mass index, renal function, lipid profiles, systolic blood pressure, metformin usage, smoking history, education level, Geriatric Depression Scale score, and presence of APOEɛ4 allele., Conclusion: Ethnic-specific R192H variation in PAX4 is associated with attention-specific cognitive impairment in Chinese with T2DM. Pending further validation studies, determining PAX4 R192H genotype may be helpful for early risk assessment of early-onset T2DM and cognitive impairment to improve diabetes care.

Introduction: The risk for diabetes progression varies greatly in individuals with type 2 diabetes mellitus (T2DM). We aimed to study the clinical determinants of diabetes progression in multiethnic Asians with T2DM., Materials and Methods: A total of 2057 outpatients with T2DM from a secondary-level Singapore hospital were recruited for the study. Diabetes progression was defined as transition from non-insulin use to requiring sustained insulin treatment or glycated haemoglobin (HbA1c) ≥8.5% when treated with 2 or more oral hypoglycaemic medications. Multivariable logistic regression (LR) was used to study the clinical and biochemical variables that were independently associated with diabetes progression. Forward LR was then used to select variables for a parsimonious model., Results: A total of 940 participants with no insulin use or indication for insulin treatment were analysed. In 3.2 ± 0.4 (mean ± SD) years' follow-up, 163 (17%) participants experienced diabetes progression. Multivariable LR revealed that age at T2DM diagnosis (odds ratio [95% confidence interval], 0.96 [0.94-0.98]), Malay ethnicity (1.94 [1.19-3.19]), baseline HbA1c (2.22 [1.80-2.72]), body mass index (0.96 [0.92-1.00]) and number of oral glucose-lowering medications (1.87 [1.39-2.51]) were independently associated with diabetes progression. Area under receiver operating characteristic curve of the parsimonious model selected by forward LR (age at T2DM diagnosis, Malay ethnicity, HbA1c and number of glucose-lowering medication) was 0.76 (95% CI, 0.72-0.80)., Conclusion: Young age at T2DM diagnosis, high baseline HbA1c and Malay ethnicity are independent determinants of diabetes progression in Asians with T2DM. Further mechanistic studies are needed to elucidate the pathophysiology underpinning progressive loss of glycaemic control in patients with T2DM.

Background: Haptoglobin (Hp) is an abundant plasma protein with anti-oxidant properties. Hp polymorphism is associated with cardio-metabolic dysfunction but the allele conferring risk of developing acute myocardial infarction (AMI) in type 2 diabetes (T2D) patients is unclear. This study aimed to investigate the association of Hp phenotype (Hp 1-1, 2-1 and 2-2) with incident AMI in Chinese T2D patients., Methods: This prospective study included Chinese T2D participants from the Singapore Study of Macro-angiopathy and Micro-vascular Reactivity in Type 2 Diabetes (SMART2D) and Diabetic Nephropathy (DN) cohorts. Information on incidence of non-fatal AMI was collected by data linkage with the Singapore Myocardial Infarction Registry. Hp phenotype was determined using enzyme-linked immunosorbent assay. Cox proportional hazards regression models were used to evaluate the association of Hp phenotype with incident AMI, adjusted for traditional risk factors separately in two cohorts, then meta-analysed., Results: In total, 2324 Chinese participants (SMART2D; N = 1034, mean age [SD] of 59 [11]) and (DN: N = 1290, mean age [SD] of 58 [12]) were included in this study. There were total of 30 (56 events per 10,000 patient-years) and 99 (128 events per 10,000 patient-years) AMI events in SMART2D and DN cohorts respectively. In meta-analysis, presence of Hp 1 allele conferred 43% (hazard ratio [HR] = 1.43 [95% CI 1.10-1.87], P = 0.008, P het  = 0.413) increased risk of incident AMI, independent of age, sex, smoking, body mass index, HbA1c, diabetes duration, lipids, hypertension, renal function and usage of insulin and RAS antagonist. In adjusted model, compared to Hp 2-2 groups, individuals with Hp 1-1 (HR = 2.18 [95% CI 1.19-3.76], P = 0.010, P het  = 0.193) and Hp 2-1 (HR = 1.45 [95% CI 0.98-2.14], P = 0.065, P het  = 0.576) were at a higher risk of incident AMI. Moreover, compared to Hp 2-2 groups, non-Hp 2-2 groups (Hp 1-1 and Hp 2-1) were at 55% increased risk of incident AMI (HR = 1.55 [95% CI 1.07-2.24], P = 0.021, P het  = 0.940)., Conclusions: Hp 1-1 phenotype was associated with increased risk of incident AMI, independent of traditional risk factors, in Chinese patients with T2D. Hp phenotyping may allow for identification of T2D individuals at higher risk for onset of AMI. However, further studies are needed to understand the underlying mechanism between Hp alleles and risk for AMI.